Function and physiology of renal KCNK channels The Research: Potassium channels allow the passive movement of potassium ions across the cell membrane. 2P domain potassium (KCNK or K2P) channels constitute a recently discovered superfamily of potassium channels. Structurally, they differ from the other potassium channels by the presence of two pore-forming loops within one channel subunit. Functionally, they differ by their ability to pass potassium at all voltages and are thus also called potassium-selective leak channels. In vivo studies of renal tubules have observed potassium leak conductances, which are involved in important functions. These include 1) the maintenance of the cell-negative potential providing the driving force for charged solute transport across the tubular membrane; 2) potassium recycling in the thick ascending limb of the loop of Henle, where it is necessary for sodium reabsorption and 3) maintenance of potassium homeostasis. These leak conductances have yet eluded molecular identification. We have determined the segment-specific expression of K2P channel transcripts in human nephron and identified three subunits with significant expression. We propose to refine the localization of these channels by immunohistochemistry and study their functional properties in heterologous expression systems. These investigations will provide a foundation for the ultimate goal: to identify KCNK channels in vivo to study their physiologic role in the context of the whole tubular cell. A thorough understanding of their physiologic function will allow identification of their potential role in disease and may establish new pharmaceutical targets for the regulation of renal function. The candidate: The candidate is a pediatric nephrologist with a goal of pursuing a career in academic medicine. He currently is at a crucial point of his research career: establishing independence. Funds provided by this proposal, if approved, would support the investigator at this critical stage of developing his own research identity. His previous research concerned the structure/function analysis of a specific K2P channel. In the studies proposed here he applies the acquired skills to his specific field of interest, renal physiology. By concentrating on this area he hopes to achieve his goal as a physician-scientist: fertile interactions between scientific investigations and clinical practice.